The present invention relates to the use of certain potent epothilone analogs in the treatment of tumors that have demonstrated resistance to therapy with other chemotherapeutic agents.
Epothilones are macrolide compounds that find utility in the pharmaceutical field. For example, epothilones A and B having the structures:
may be found to exert microtubule-stabilizing effects similar to paclitaxel (TAXOL(copyright)) and hence cytotoxic activity against rapidly proliferating cells, such as tumor cells or other hyperproliferative cellular disease, see Hofle et al., Angew. Chem. Int. Ed. Engl., Vol. 35, No.13/14, 1567-1569 (1996); WO93/10121 published May 27, 1993; and WO97/19086 published May 29, 1997.
Derivatives and analogs of epothilones A and B have been synthesized and may be used to treat a variety of cancers and other abnormal proliferative diseases. Such analogs are disclosed in Hofle et al., Id.; Nicolaou et al., Angew. Chem. Int. Ed. Engl., Vol. 36, No. 19, 2097-2103 (1997); and Su et al., Angew. Chem. Int. Ed. Engl., Vol. 36, No. 19, 2093-2097 (1997). In some instances, epothilone derivatives have demonstrated enhanced properties over the original epothilones A and B. The present invention is concerned with the discovery that two such epothilone derivatives may be utilized to treat certain cancers that have demonstrated resistance to other chemotherapeutic agents, such as oncolytic agents of the taxane family of compounds.
In accordance with the present invention, tumors demonstrating a clinical resistance to treatment with taxane oncology agents may be treated with an epothilone derivative selected from those represented by formula I: 
wherein G, P, Q and R have the meanings given below. The compounds represented by formula I have previously demonstrated significantly enhanced potency over other known chemotherapeutic agents, for example, epothilones A and B above and certain others including those in the taxane series. The compounds represented by formula I are further advantageous in that, unlike most oncology agents, they are efficacious via oral administration.